For people who have lost all or most of their kidney or liver functions, it is necessary to find alternative ways of cleaning the blood. One common alternative is dialysis, in which the waste products in the blood are transported across a membrane to a cleaning fluid. In hemodialysis, the most common form of dialysis, blood is removed from the body, and is led to an external device, the dialyzer, which contains a membrane with blood flowing on one side and a dialysis fluid flowing on the other side of the membrane. The blood is then returned to the body. Due to the concentration difference between the blood and the dialysis fluid across the membrane, waste products in the blood will be transported by diffusion to the dialysis fluid. At the same time any excess fluid may be removed by ultrafiltration, which is achieved by creating a pressure difference across the membrane.
This dialysis procedure can be very effective for substances that are dissolved in the body fluids, including the blood plasma. The driving force for the transport across the membrane is the concentration difference, and as long as this concentration difference is maintained, the transport rate can be high. For substances with a zero concentration in the dialysis fluid, the transport rate can be calculated as the product of the blood concentration and a factor known as the dialyzer clearance. The clearance value can be viewed as the fraction of the blood flow that is totally cleared from the substance in question, and is measured in ml/min.
The main determinants for the clearance (Cl) are the flow rates of blood (Qb) and dialysis fluid (Qd), and the transport capacity of the membrane. The membrane can be characterized by its mass transfer coefficient, koA, which is proportional to the membrane area, and can be interpreted as the clearance that would be obtained at very large flow rates of blood and dialysis fluid. An equation for the dialyzer clearance can be derived theoretically by calculating the concentration profiles along the dialyzer. Considering a mass balance at each point along the dialyzer, taking into account the mass transported by the flows, and the diffusion across the membrane, leads to a set of differential equations for the concentrations along the dialyzer in the direction of the blood flow. The mass removal rate needed for the calculation of clearance is then obtained from the blood flow rate and the calculated change in the blood concentration. In the absence of any ultrafiltration clearance is given by equation 1
                    Cl        =                              Q            b                    ·                                                    (                                  1                  -                                      ⅇ                    f                                                  )                            ·                              Q                d                                                                    Q                d                            -                                                Q                  b                                ·                                  ⅇ                  f                                                                                        (        1        )            wherein e denotes the exponential function, and the exponent f is calculated from equation 2
                    f        =                              k            o                    ⁢                      A            ⁡                          (                                                1                                      Q                    d                                                  -                                  1                                      Q                    b                                                              )                                                          (        2        )            
For the derivation of equations 1 and 2 it is assumed that both blood and dialysis fluid are perfectly mixed at each point along the dialyzer. The concentration is thus assumed to vary along the dialyzer according to the calculated concentration profiles, but the concentrations are assumed to be independent of the distance from the membrane. It is also assumed that the flows are equally distributed in the whole dialyzer. Even with these limitations the equations have been shown in practice to well describe the dependence of clearance on the flow rates of blood and dialysis fluid. These equations, with a correction for ultrafiltration when needed, are therefore often used to describe the capacity of dialyzers.
A closer study of equations 1 and 2 reveals that the clearance can never exceed either of Qb, Qd, or koA. The dialysis fluid flow rate Qd and the koA are limited only by the available equipment, but the blood flow rate is limited by the rate at which blood can be obtained from the blood access in the patient. This is for dialysis normally in the range 200-500 ml/min. This limits the maximum efficiency that can be obtained in dialysis treatments, and has lead to fairly standardized values for Qd and membrane koA used in normal dialysis treatments, since the cost of higher flow rates and koA cannot be justified by a better efficiency.
If Qd is increased when Qb and koA are fixed, clearance will increase to a certain fraction of the blood flow rate, which is determined by koA. Already at a Qd of twice the blood flow rate clearance is close to this limit, and little is gained by going higher. Dialysis fluid flow rates in standard hemodialysis are therefore normally in the range 500-800 ml/min.
If instead koA is increased when Qd and Qb are fixed, clearance will approach Qb independently of Qd (as long as Qd is higher than Qb). The increase is noticeable even at koA values up to 3-4 times the blood flow rate, but for economical and practical reasons dialyzer koA values in standard hemodialysis are usually limited to the range 500-1000 ml/min.
The analysis above is valid for substances that are dissolved in fluids such as plasma. But many substances are to a large extent bound to carriers such as albumin. Examples of substances that can bind to albumin are butyric and valeric acid, thyroxine, tryptophane, unconjugated bilirubin, mercaptans, and aromatic amino acids. A number of drugs are known to have a high binding rate to albumin in cases of accidental overdosage or suicidal intoxications by e.g. tricyclic antidepressants, digoxin, digitoxin, theophylline or a benzodiazepine.
Hemoglobin may also act as a carrier, e.g. for carbon monoxide or cyanide. These substances have a high affinity to hemoglobin, and will replace oxygen, which significantly decreases the ability of the blood to transport oxygen.
In many cases it may be important to have a high removal rate also for substances in the blood that to a large extent are bound to proteins or other carriers, such as fungus toxins. But the situation is different from that of the dissolved substances discussed above. Even with a large total amount of partly protein bound and partly dissolved substance in the blood, the plasma concentration may be low, since most of the substance may be bound. The concentration gradient across the membrane will then be small, so that the transport rate in dialysis will be low, as will the treatment efficiency.
Previous attempts to solve this problem have focused on adding a carrier to the dialysis fluid as well. For albumin bound toxins, a common solution is to add albumin to the dialysis fluid. Substances transported across the membrane into the dialysis fluid will then bind to the albumin in the dialysis fluid. This will keep the concentration low in the dialysis fluid, so that the transport across the membrane can continue without a disappearing concentration gradient. The capacity of the dialysis fluid to carry protein bound substances thus becomes much greater, see e.g. U.S. Pat. No. 5,744,042.
With most of the substance bound to carriers, the concentration gradient is still small, and even better results may be achieved if the membrane itself is also modified to enhance the transport. This has been suggested in U.S. Pat. No. 5,744,042, where the membrane is primed with albumin so that the inner and outer membrane surfaces are covered with albumin, which adheres to the surfaces. Thus, sites are created within the membrane that can act as mediators for the transport across the membrane.
A major disadvantage with adding a carrier like albumin to the dialysis fluid and/or to the membrane is that it is very expensive. It is therefore desirable not to waste this dialysis fluid including albumin. In U.S. Pat. No. 5,744,042 it is suggested to put a cleaning cartridge in the dialysis loop that will remove the bound substances from the carrier to regenerate the dialysis fluid. By doing so only a small amount of dialysis fluid is needed since it can be reused over and over again. The problem is that this fluid will be saturated with all the solutes that are not removed by the cartridge, and it was therefore necessary to introduce a second loop of dialysis in order to clean the primary dialysis fluid, and also to remove any excess fluid that is normally accumulated in a patient between treatments.